This application is a national stage filing of PTC international Application No. PCT/FI01/00265, filed on Mar. 16, 2001. This application also claims the benefit of priority under 35 U.S.C. xc2xa7119(a) to Finnish patent application no. 20000635, filed on Mar. 17, 2000.
The invention relates to the use of catechol-O-methyl transferase (COMT) inhibitors in the treatment or control of pain in mammals.
Analgesic drugs can be divided into three groups: the nonopioid analgesics, the opioid analgesics and the adjuvant analgesics. The nonopioid analgesics such as aspirin, paracetamol and the nonsteroidal anti-inflammatory drugs (NSAIDs) like indomethacin and ibuprofen, act peripherally and in some cases also centrally through inhibition of various enzymes, mainly cyclooxygenase. The inhibition of cyclooxygenase leads to reduction in the hyperalgesic prostaglandins. The opioid analgesics produce analgesia through binding to the opiate receptors in the central nervous system. Adjuvant analgesics increase the analgesic effects of the opioids or act as analgesics themselves. This group of drugs include miscellaneous drugs e.g. anticonvulsants like carbamazepine, tricyclic antidepressants, steroids etc.
Inhibitors of catechol-O-methyl transferase (COMT) as well as methods for the preparation thereof are known in the prior art, e.g. in GB-A-2 200 109, EP-A-237 929 and WO-A-96 37456 as well as i.a. in British Journal of Pharmacology, vol.126, 1999, p.1667-1673 (E. Rivas et al.), in Journal of Medical Chemistry, vol.35(24), 1992, p.4584-4588 (R. A. Pxc3xa9rez et al.) and in Biochemical Pharmacology, vol.45(10), 1993, p.1973-1981 (R. A. Pxc3xa9rez et al.).
COMT is an enzyme which metabolises i.a. endogenous sympathomimetic catecholamines like dopamine and noradrenaline. COMT enzyme metabolises also exogenously adminstered catecholamines, e.g. levodopa. The inhibitors of COMT have been used i.a. in the treatment of Parkinson""s disease for inhibiting the metabolism of levodopa. As specific examples i.a. entacapone ((E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propenamide) and tolcapone (3,4-dihydroxy-4xe2x80x2-methyl-5-nitrobenzophenone) can be mentioned.
Furthermore, WO-A-98 27973 describes the use of the COMT inhibitors, especially nitecapone (3-(3,4-dihydroxy-5-nitrophenyl)methylene-2,4-pentanedione), in the prevention of diabetic vascular dysfunctions. Nitecapone is also known to have a natriuretic effect (Eklxc3x6f et al. J. Am. Soc. Nephrology 5 (3), 657, 1994, Holtbxc3xa4ck et al., J. Am. Soc. Nephrology, 7(9), 1633, 1996).
U.S. Pat. No. 5,489,614 discloses catechol derivatives useful as antioxidants in the prevention or treatment of tissue damage induced by lipid peroxidation.
The object of the invention is to provide further use of the COMT inhibitors, i.e. the use of COMT inhibitors in the treatment or control of pain in mammals, including animals and human beings.